Aging effects on DNA methylation modules in human brain and blood tissue
Steve Horvath, Yafeng Zhang, Peter Langfelder, René S Kahn, Marco P M Boks, Kristel van Eijk, Leonard H van den Berg, Roel A Ophoff, Steve Horvath, Yafeng Zhang, Peter Langfelder, René S Kahn, Marco P M Boks, Kristel van Eijk, Leonard H van den Berg, Roel A Ophoff
Abstract
Background: Several recent studies reported aging effects on DNA methylation levels of individual CpG dinucleotides. But it is not yet known whether aging-related consensus modules, in the form of clusters of correlated CpG markers, can be found that are present in multiple human tissues. Such a module could facilitate the understanding of aging effects on multiple tissues.
Results: We therefore employed weighted correlation network analysis of 2,442 Illumina DNA methylation arrays from brain and blood tissues, which enabled the identification of an age-related co-methylation module. Module preservation analysis confirmed that this module can also be found in diverse independent data sets. Biological evaluation showed that module membership is associated with Polycomb group target occupancy counts, CpG island status and autosomal chromosome location. Functional enrichment analysis revealed that the aging-related consensus module comprises genes that are involved in nervous system development, neuron differentiation and neurogenesis, and that it contains promoter CpGs of genes known to be down-regulated in early Alzheimer's disease. A comparison with a standard, non-module based meta-analysis revealed that selecting CpGs based on module membership leads to significantly increased gene ontology enrichment, thus demonstrating that studying aging effects via consensus network analysis enhances the biological insights gained.
Conclusions: Overall, our analysis revealed a robustly defined age-related co-methylation module that is present in multiple human tissues, including blood and brain. We conclude that blood is a promising surrogate for brain tissue when studying the effects of age on DNA methylation profiles.
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References
- Guarente L. Do changes in chromosomes cause aging? Cell. 1996;13:9–12. doi: 10.1016/S0092-8674(00)80072-0.
- Wareham KA, Lyon MF, Glenister PH, Williams ED. Age related reactivation of an X-linked gene. Nature. 1987;13:725–727. doi: 10.1038/327725a0.
- Berdyshev G, Korotaev G, Boiarskikh G, Vaniushin B. Nucleotide composition of DNA and RNA from somatic tissues of humpback and its changes during spawning. Biokhimiia. 1967;13:88–993.
- Bell JT, Tsai P-C, Yang T-P, Pidsley R, Nisbet J, Glass D, Mangino M, Zhai G, Zhang F, Valdes A, Shin S-Y, Dempster EL, Murray RM, Grundberg E, Hedman AK, Nica A, Small KS, Dermitzakis ET, McCarthy MI, Mill J, Spector TD, Deloukas P, The Mu TC. Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population. PLoS Genet. 2012;13:e1002629. doi: 10.1371/journal.pgen.1002629.
- Wilson V, Jones P. DNA methylation decreases in aging but not in immortal cells. Science. 1983;13:1055–1057. doi: 10.1126/science.6844925.
- Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekström TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP. Intra-individual Change Over Time in DNA Methylation With Familial Clustering. JAMA: The Journal of the American Medical Association. 2008;13:2877–2883. doi: 10.1001/jama.299.24.2877.
- Boks MP, Derks EM, Weisenberger DJ, Strengman E, Janson E, Sommer IE, Kahn RS, Ophoff RA. The Relationship of DNA Methylation with Age, Gender and Genotype in Twins and Healthy Controls. PLoS ONE. 2009;13:e6767. doi: 10.1371/journal.pone.0006767.
- Alisch RS, Barwick BG, Chopra P, Myrick LK, Satten GA, Conneely KN, Warren ST. Age-associated DNA methylation in pediatric populations. Genome Res. 2012;13:623–632. doi: 10.1101/gr.125187.111.
- Fraga MF, Agrelo R, Esteller M. Cross-Talk between Aging and Cancer. Annals of the New York Academy of Sciences. 2007;13:60–74. doi: 10.1196/annals.1395.005.
- Fraga MF, Esteller M. Epigenetics and aging: the targets and the marks. Trends in Genetics. 2007;13:413–418. doi: 10.1016/j.tig.2007.05.008.
- Rodríguez-Rodero S, Fernández-Morera J, Fernandez A, Menéndez-Torre E, Fraga M. Epigenetic regulation of aging. Discov Med. 2010;13:225–233.
- Mugatroyd C, Wu Y, Bockmühl Y, Spengler D. The Janus face of DNA methylation in aging. AGING. 2010. p. 2.
- Murgatroyd C, Patchev AV, Wu Y, Micale V, Bockmuhl Y, Fischer D, Holsboer F, Wotjak CT, Almeida OFX, Spengler D. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci. 2009;13:1559–1566. doi: 10.1038/nn.2436.
- Christensen B, Houseman E, Marsit C, Zheng S, Wrensch M, Wiemels J, Nelson H, Karagas M, Padbury J, Bueno R, Sugarbaker D, Yeh R, Wiencke J, Kelsey K. Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context. PLoS Genet. 2009;13:e1000602. doi: 10.1371/journal.pgen.1000602.
- Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, Beyan H, Whittaker P, McCann OT, Finer S, Valdes AM, Leslie RD, Deloukas P, Spector TD. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res. 2010;13:434–439. doi: 10.1101/gr.103101.109.
- Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, Shen H, Campan M, Noushmehr H, Bell CG, Maxwell AP, Savage DA, Mueller-Holzner E, Marth C, Kocjan G, Gayther SA, Jones A, Beck S, Wagner W, Laird PW, Jacobs IJ, Widschwendter M. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010;13:440–446. doi: 10.1101/gr.103606.109.
- Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006;13:349–353. doi: 10.1038/nature04733.
- Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K-i, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP, Melton DA, Gifford DK, Jaenisch R, Young RA. Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells. Cell. 2006;13:301–313. doi: 10.1016/j.cell.2006.02.043.
- Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, Lai S-L, Arepalli S, Dillman A, Rafferty IP, Troncoso J, Johnson R, Zielke HR, Ferrucci L, Longo DL, Cookson MR, Singleton AB. Abundant Quantitative Trait Loci Exist for DNA Methylation and Gene Expression in Human Brain. PLoS Genet. 2010;13:e1000952. doi: 10.1371/journal.pgen.1000952.
- Numata S, Ye T, Hyde Thomas M, Guitart-Navarro X, Tao R, Wininger M, Colantuoni C, Weinberger Daniel R, Kleinman Joel E, Lipska Barbara K. DNA Methylation Signatures in Development and Aging of the Human Prefrontal Cortex. The American Journal of Human Genetics. 2012;13:260–272. doi: 10.1016/j.ajhg.2011.12.020.
- Cai C, Langfelder P, Fuller TF, Oldham MC, Luo R, van den Berg LH, Ophoff RA, Horvath S. Is human blood a good surrogate for brain tissue in transcriptional studies? BMC Genomics. 2010;13:589. doi: 10.1186/1471-2164-11-589.
- Stolzenberg DS, Grant PA, Bekiranov S. Epigenetic methodologies for behavioral scientists. Hormones and Behavior. 2011;13:407–416. doi: 10.1016/j.yhbeh.2010.10.007.
- Horvath S. Weighted Network Analysis Applications in Genomics and Systems Biology. Springer; 2011.
- Langfelder P, Luo R, Oldham MC, Horvath S. Is My Network Module Preserved and Reproducible? PLoS Comput Biol. 2011;13:e1001057. doi: 10.1371/journal.pcbi.1001057.
- Miller JA, Cai C, Langfelder P, Geschwind DH, Kurian SM, Salomon DR, Horvath S. Strategies for aggregating gene expression data: The collapseRows R function. BMC Bioinformatics. 2011;13:322. doi: 10.1186/1471-2105-12-322.
- Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA. A Transcriptome Database for Astrocytes, Neurons, and Oligodendrocytes: A New Resource for Understanding Brain Development and Function. The Journal of Neuroscience. 2008;13:264–278. doi: 10.1523/JNEUROSCI.4178-07.2008.
- Siegmund KD, Connor CM, Campan M, Long TI, Weisenberger DJ, Biniszkiewicz D, Jaenisch R, Laird PW, Akbarian S. DNA Methylation in the Human Cerebral Cortex Is Dynamically Regulated throughout the Life Span and Involves Differentiated Neurons. PLoS ONE. 2007;13:e895. doi: 10.1371/journal.pone.0000895.
- Parachikova A, Agadjanyan MG, Cribbs DH, Blurton-Jones M, Perreau V, Rogers J, Beach TG, Cotman CW. Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiology of aging. 2007;13:1821–1833. doi: 10.1016/j.neurobiolaging.2006.08.014.
- Swerdlow RH. Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiology of aging. 2007;13:1465–1480. doi: 10.1016/j.neurobiolaging.2006.06.021.
- Groen T. In: DNA Methylation and Alzheimer's Disease Epigenetics of Aging. Tollefsbol TO, editor. Springer New York; 2010. pp. 315–326.
- Irier H, Jin P. Dynamics of DNA Methylation in Aging and Alzheimer's Disease. DNA Cell Biol. 2012.
- Aging related methylation modules: R software tutorials and data.
- Song H, Ramus SJ, Tyrer J, Bolton KL, Gentry-Maharaj A, Wozniak E, Anton-Culver H, Chang-Claude J, Cramer DW, DiCioccio R, Dork T, Goode EL, Goodman MT, Schildkraut JM, Sellers T, Baglietto L, Beckmann MW, Beesley J, Blaakaer J, Carney ME, Chanock S, Chen Z, Cunningham JM, Dicks E, Doherty JA, Durst M, Ekici AB, Fenstermacher D, Fridley BL, Giles G. et al.A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet. 2009;13:996–1000. doi: 10.1038/ng.424.
- Bork S, Pfister S, Witt H, Horn P, Korn B, Ho A, Wagner W. DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging Cell. 2010;13:54–63. doi: 10.1111/j.1474-9726.2009.00535.x.
- Schellenberg A, Lin Q, Schuler H, Koch C, Joussen S, Denecke B, Walenda G, Pallua N, Suschek C, Zenke M, Wagner W. Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks. Aging (Albany NY) 2011;13:873–888.
- Weisenberger D, den Berg D, Pan F, Berman B, Laird P. Comprehensive DNA methylation analysis on the Illumina Infinium assay platform. Technical report Illumina, Inc, San Diego. 2008.
- Dunning M, Barbosa-Morais N, Lynch A, Tavare S, Ritchie M. Statistical issues in the analysis of Illumina data. BMC Bioinformatics. 2008;13:85. doi: 10.1186/1471-2105-9-85.
- Chen Y, Choufani S, Ferreira J, Grafodatskaya D, Butcher D, Weksberg R. Sequence overlap between autosomal and sex-linked probes on the Illumina HumanMethylation27 microarray. Genomics. 2011;13:214–222. doi: 10.1016/j.ygeno.2010.12.004.
- Whitlock M. Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach. J Evolutionary Biology. 2005;13:1368. doi: 10.1111/j.1420-9101.2005.00917.x.
- Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences of the United States of America. 2003;13:9440–9445. doi: 10.1073/pnas.1530509100.
- Almaas E. Biological impacts and context of network theory. J Exp Biol. 2007;13:1548–1558. doi: 10.1242/jeb.003731.
- Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Statistical Applications in Genetics and Molecular Biology. 2005. p. 4.
- Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, Laurance MF, Zhao W, Qi S, Chen Z, Lee Y, Scheck AC, Liau LM, Wu H, Geschwind DH, Febbo PG, Kornblum HI, Cloughesy TF, Nelson SF, Mischel PS. Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proceedings of the National Academy of Sciences. 2006;13:17402–17407. doi: 10.1073/pnas.0608396103.
- Ravasz E, Somera AL, Mongru DA, Oltvai ZN, Barabasi AL. Hierarchical organization of modularity in metabolic networks. Science. 2002;13:1551–1555. doi: 10.1126/science.1073374.
- Yip AM, Horvath S. Gene network interconnectedness and the generalized topological overlap measure. BMC Bioinformatics. 2007;13:22. doi: 10.1186/1471-2105-8-22.
- Song L, Langfelder P, Horvath S. Comparison of co-expression measures: mutual information, correlation, and model based indices. UCLA Technical Report Submitted. 2012.
- Langfelder P, Horvath S. Eigengene networks for studying the relationships between co-expression modules. BMC Systems Biology. 2007;13:54. doi: 10.1186/1752-0509-1-54.
- Li A, Horvath S. Network neighborhood analysis with the multi-node topological overlap measure. Bioinformatics. 2007;13:222–231. doi: 10.1093/bioinformatics/btl581.
- Allen J, Xie Y, Chen M, Girard L, Xiao G. Comparing Statistical Methods for Constructing Large Scale Gene Networks. PLoS ONE. 2012;13:e29348. doi: 10.1371/journal.pone.0029348.
- Langfelder P, Zhang B, Horvath S. Defining clusters from a hierarchical cluster tree: the Dynamic Tree Cut library for R. Bioinformatics. 2007. November:btm563.
- Horvath S, Dong J. Geometric Interpretation of Gene Coexpression Network Analysis. PLoS Comput Biol. 2008;13:e1000117. doi: 10.1371/journal.pcbi.1000117.
- Margolin A, Nemenman I, Basso K, Wiggins C, Stolovitzky G, Favera R, Califano A. ARACNE: An Algorithm for the Reconstruction of Gene Regulatory Networks in a Mammalian Cellular Context. BMC Bioinformatics. 2006;13:S7.
- Smith V, Yu J, Smulders T, Hartemink A, Jarvis E. Computational Inference of Neural Information Flow Networks. PLoS Computational Biology. 2006. p. 2.
- Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;13:559. doi: 10.1186/1471-2105-9-559.
- Hosack DA, Dennis G Jr, Sherman BT, Lane HC, Lempicki RA. Identifying biological themes within lists of genes with EASE. Genome Biol. 2003;13:R70. doi: 10.1186/gb-2003-4-10-r70.
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